The morbidity and mortality associated with obesity is a major health problem in the VA patient population. There is abundant evidence that obesity confers increased risk for various forms of cancer. The VA reports ~40,000 new cases of cancer per year and ~2.7-3% are liver cancer. Obesity is associated with metabolic disturbances such as non-alcoholic fatty liver disease (NAFLD) and its more severe form non- alcoholic steatosis (NASH) and these are risk factors for both cirrhosis and liver cancer. So chronic liver disease, whether induced by viral infection, alcohol use, obesity or any combination thereof, is the major risk factor for cirrhosis and ultimately liver cancer. The Veteran population is at high risk for obesity-associated liver disease and hence liver cancer so it is important to understand the etiology and pathogenesis of the disease. Similarly the incidence of breast cancer is increased in obese populations, and the epidemiologic evidence for the obesity-breast cancer connection is particularly strong in post-menopausal women. One in eight women will be diagnosed with breast cancer during their lifetime. As increasing numbers of women enter military service, women?s health issues become a greater concern for the VA. Battlefield exposures to toxicants and bad nutrition may trigger the metabolic syndrome that is associated with higher risk of heart disease, diabetes and cancer. Studies to understand how environmental and nutritional events impact the regulation of normal metabolism will shed greater light on how metabolic dysregulation increases the risk of various diseases. We have found that reducing inflammation and insulin resistance reduces breast cancer growth in mice. This can be done by providing high levels of omega3 fatty acids or through a nutritional intervention involving time-restricted feeding of a high-fat diet. Due to the link between obesity, insulin resistance and breast cancer risk in post-menopausal women, and the potential that a similar time-restricted, dietary intervention could protect against breast cancer in humans, it is important to understand how correcting insulin resistance reduces the risk of breast cancer growth in mice and investigate the physiological changes that may drive tumor growth in obesity. We have published that loss of a particular RNA splicing factor SRSF3 in hepatocytes causes chronic liver damage, disruptions in glucose and lipid metabolism, inflammation, fibrosis, and eventually liver cancer. So the loss of the splicing factor does not cause tumors but rather creates a pre-disposition to cancer, similar to a tumor suppressor gene. We have since shown that loss of SRSF3 is found in early liver disease in both humans and mice, in addition to being lost in liver cancer, so loss of SRSF3 may be the precipitating event that triggers progressive liver disease. Our studies will address key questions concerning the fundamental biological process of protein homeostasis and carcinogenesis in the liver and will integrate biochemical, cell and molecular biological experiments with physiological studies in mice lacking specific splicing factors in liver. We will investigate whether preventing degradation of SRSF3 in mice is sufficient to prevent the progression of early liver disease to inflammation, fibrosis and cirrhosis, and we will determine whether this approach prevents liver cancer or can be used to reverse liver cancer in mice. Lastly, obesity is associated with tissue inflammation and we have shown that altering cAMP levels in dendritic cells changes their ability to instruct T cells to develop into Th2 or Th17 lineages. This has important metabolic consequences as a Th2 bias prevents high-fat diet induced obesity and insulin resistance. We furthermore found that induction of a Th17 biased inflammation accelerates lung cancer in mice, and loss of IL- 17A prevents tumor growth. Our studies are designed to understand the link between inflammation and metabolism, and how these alter lung cancer growth. This is an important area of research for the VA patient population as smoking is common among veterans.